We have long advocated the use of gene expression datasets for understanding the mechanisms underlying complex human disease, and we believe that the unique nature of data in the Genotype-Tissue Expression (GTEx) program will allow us to enhance our understanding of the functionality for a large class of variants, will lead to great insight into the genetic components of common diseases, and will permit the exploration of several novel scientific hypotheses on both transcriptome biology and the genetic architecture of human disease. The opportunity to analyze the GTEx datasets motivates the development of new statistical methods, software and knowledge databases that will facilitate the use of these results by the larger scientific community for additional investigations. All proposed research is informed by our near-complete immersion in studies relating genotype to phenotype (and in developing methods for relating genotype to phenotype) for many different complex traits. Thus, our specific aims are: 1) to discover cross-tissue and tissue-specific regulatory variation and to use the resulting information for discovery of novel risk pathways, and for partitioning of disease heritability into components corresponding to different classes of functional variants; 2) to test hypotheses that are finally feasible to investigate due to the uniqe design of the GTEx program, including the role of gender and other environmental exposures on regulatory variation, and the role of loss of function and missense variants in transcription; and 3) to use systems and network approaches for a better understanding of the organization of gene expression across tissues. All software and the databases developed through this project will be made publicly available immediately.